Discovery of Novel, Potent Benzamide Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model

We report the discovery of potent benzamide inhibitors of 11β-hydroxysteroid dehydrogenase (11β-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a f...

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Veröffentlicht in:	Journal of medicinal chemistry 2008-07, Vol.51 (13), p.3953-3960
Hauptverfasser:	Julian, Lisa D, Wang, Zhulun, Bostick, Tracy, Caille, Seb, Choi, Rebekah, DeGraffenreid, Michael, Di, Yongmei, He, Xiao, Hungate, Randall W, Jaen, Juan C, Liu, Jinsong, Monshouwer, Mario, McMinn, Dustin, Rew, Yosup, Sudom, Athena, Sun, Daqing, Tu, Hua, Ursu, Stefania, Walker, Nigel, Yan, Xuelei, Ye, Qiuping, Powers, Jay P
Format:	Artikel
Sprache:	eng
Schlagworte:	Biological and medical sciences General and cellular metabolism. Vitamins Medical sciences Pharmacology. Drug treatments
Online-Zugang:	Volltext
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Zusammenfassung:	We report the discovery of potent benzamide inhibitors of 11β-hydroxysteroid dehydrogenase (11β-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11β-HSD1 activity in a monkey ex vivo pharmacodynamic model.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm800310g